Harmine Alleviated Sepsis-Induced Cardiac Dysfunction by Modulating Macrophage Polarization via the STAT/MAPK/NF-κB Pathway DOI Creative Commons
Weibin Ruan, Xinyun Ji, Yating Qin

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 9

Published: Jan. 17, 2022

Sepsis is a dysregulated systemic inflammatory response that often leads to cardiac dysfunction, which termed sepsis-induced cardiomyopathy (SIC). Harmine, natural β-carboline alkaloid compound, has been shown exert pharmacological effects on several diseases. Here, we investigated whether harmine protected against SIC development and the underlying mechanisms. In vitro, expression of M1 phenotype markers iNOS COX-2 was increased in RAW 264.7 cells stimulated with lipopolysaccharide (LPS), but this effect reversed by intervention. Furthermore, LPS-induced increases levels cytokines, including IL-1β, IL-6, TNF-α, iNOS, COX-2, PGE2 TXB2, generated macrophages were suppressed when pretreated harmine. Meanwhile, our findings showed administration effectively attenuated inflammation apoptosis H9c2 proinflammatory environment produced macrophages, as evidenced reductions NLRP3 cleaved caspase 3 p-NF-κB/NF-κB ratio. The western blot results indicated mechanisms harmine-mediated inhibition polarization might be associated suppression STAT1/3, NF-κB MAPK activation. an LPS injection induced dysfunction decreased survival rate mice, alleviated treatment, relevant mechanism possibly attributed drug-induced attenuation apoptotic processes cardiomyocytes. Collectively, these implied treatment suppressing phenotypic macrophages.

Language: Английский

Sepsis induces interleukin 6, gp130/JAK2/STAT3, and muscle wasting DOI Creative Commons
Lukas Zanders, Melanie Kny, Alexander Hahn

et al.

Journal of Cachexia Sarcopenia and Muscle, Journal Year: 2021, Volume and Issue: 13(1), P. 713 - 727

Published: Nov. 24, 2021

Abstract Background Sepsis and inflammation can cause intensive care unit‐acquired weakness (ICUAW). Increased interleukin‐6 (IL‐6) plasma levels are a risk factor for ICUAW. IL‐6 signalling involves the glycoprotein 130 (gp130) receptor JAK/STAT‐pathway, but its role in sepsis‐induced muscle wasting is uncertain. In clinical observational study, we found that target gene, SOCS3 , was increased skeletal of ICUAW patients indicative JAK/STAT‐pathway activation. We tested hypothesis IL‐6/gp130‐pathway mediates atrophy. Methods sequenced RNA (RNAseq) from tibialis anterior (TA) cecal ligation puncture‐operated (CLP) sham‐operated wildtype (WT) mice. The effects IL‐6/gp130/JAK2/STAT3‐pathway were investigated by analysing atrophy phenotype, gene expression, protein contents C2C12 myotubes. Mice lacking Il6st encoding gp130, myocytes (cKO) WT controls, as well mice treated with JAK2 inhibitor AG490 or vehicle exposed to CLP sham surgery 24 96 h. Results Analyses differentially expressed genes RNAseq (≥2‐log2‐fold change, P < 0.01) revealed an activation IL‐6‐signalling JAK/STAT‐signalling pathways septic mice, which occurred after h lasted at least during sepsis. treatment myotubes induced STAT3 phosphorylation (three‐fold, Socs3 mRNA expression (3.1‐fold, caused myotube Knockdown diminished IL‐6‐induced (−30.0%; 0.01), (− 29.0%; inhibition (−38.7%; 0.05) decreased expression. Treatment either attenuated response IL‐6. CLP‐operated showed TA muscle, reduced ‐cKO 67.8% ( 85.6% 0.001), respectively. loss weight, (WT: −22.3%, 0.001, cKO: −13.5%, 0.001; vs. cKO 0.001). While resulted reduction MuRF1 contents, Atrogin‐1 remained unchanged between Trim63 /MuRF1 Fbxo32 /Atrogin‐1 unaltered CLP‐treated (−22.2%, (29.6% relative weight loss, 0.05). accompanied /Atrogin‐1‐mRNA (−81.3%, /MuRF1‐mRNA (−77.6%, content. Conclusions via gp130/JAK2/STAT3‐pathway possibly contributing

Language: Английский

Citations

126
Inhibition of the NLRP3/IL‐1β axis protects against sepsis‐induced cardiomyopathy DOI
Katharina Büsch, Melanie Kny,

Nora Huang

et al.

Journal of Cachexia Sarcopenia and Muscle, Journal Year: 2021, Volume and Issue: 12(6), P. 1653 - 1668

Published: Sept. 2, 2021

Language: Английский

Citations

113
Dapagliflozin reduces systemic inflammation in patients with type 2 diabetes without known heart failure DOI Creative Commons

Dennis D. Wang,

Anna Naumova,

Daniel Isquith

et al.

Cardiovascular Diabetology, Journal Year: 2024, Volume and Issue: 23(1)

Published: June 7, 2024

Abstract Objective Sodium glucose cotransporter 2 (SGLT2) inhibitors significantly improve cardiovascular outcomes in diabetic patients; however, the mechanism is unclear. We hypothesized that dapagliflozin improves cardiac via beneficial effects on systemic and inflammation fibrosis. Research design methods This randomized placebo-controlled clinical trial enrolled 62 adult patients (mean age 62, 17% female) with type diabetes (T2D) without known heart failure. Subjects were to 12 months of daily 10 mg or placebo. For all patients, blood/plasma samples magnetic resonance imaging (CMRI) obtained at time randomization end months. Systemic was assessed by plasma IL-1B, TNFα, IL-6 ketone levels PBMC mitochondrial respiration, an emerging marker sterile inflammation. Global myocardial strain feature tracking; fibrosis T1 mapping calculate extracellular volume fraction (ECV); tissue T2 mapping. Results Between baseline 12-month point, IL-1B reduced (− 1.8 pg/mL, P = 0.003) while ketones increased (0.26 mM, 0.0001) dapagliflozin. maximal oxygen consumption rate (OCR) decreased over period placebo group but did not change receiving 158.9 pmole/min/10 6 cells, 0.0497 vs. − 5.2 0.41), a finding consistent anti-inflammatory effect SGLT2i. strain, ECV relaxation both study groups. Clinical Trial.gov Registration NCT03782259.

Language: Английский

Citations

17
Mitochondrial dysfunction is a major cause of thromboinflammation and inflammatory cell death in critical illnesses DOI Creative Commons
Toshiaki Iba, Julie Helms, Cheryl L. Maier

et al.

Inflammation Research, Journal Year: 2025, Volume and Issue: 74(1)

Published: Jan. 13, 2025

Language: Английский

Citations

2
Out of Control: The Role of the Ubiquitin Proteasome System in Skeletal Muscle during Inflammation DOI Creative Commons

Stefanie Haberecht-Müller,

Elke Krüger,

Jens Fielitz

et al.

Biomolecules, Journal Year: 2021, Volume and Issue: 11(9), P. 1327 - 1327

Published: Sept. 8, 2021

The majority of critically ill intensive care unit (ICU) patients with severe sepsis develop ICU-acquired weakness (ICUAW) characterized by loss muscle mass, reduction in myofiber size and decreased strength leading to persisting physical impairment. This phenotype results from a dysregulated protein homeostasis increased degradation synthesis, eventually causing decrease structural proteins. ubiquitin proteasome system (UPS) is the predominant protein-degrading that activated during diverse atrophy conditions, e.g., inflammation. specificity UPS-mediated assured E3 ligases, such as atrogin-1 MuRF1, which target contractile proteins, proteins involved energy metabolism transcription factors for UPS-dependent degradation. Although regulation activity function ligases inflammation-induced well perceived, contribution inflammation still elusive. During inflammation, shift standard- immunoproteasome was described; however, extent this contributes wasting whether changes targeting specific muscular not described. review summarizes main proinflammatory cytokines acute phase response their signaling pathways focus on sepsis. target-specificity mode action myofibrillar will be reported. described effects proteasome-inhibitors treatment strategies discussed.

Language: Английский

Citations

61
Molecular mechanisms and functions of pyroptosis in sepsis and sepsis-associated organ dysfunction DOI Creative Commons
Ri Wen, Yongping Liu,

Xiao-Xu Tong

et al.

Frontiers in Cellular and Infection Microbiology, Journal Year: 2022, Volume and Issue: 12

Published: July 29, 2022

Sepsis, a life-threatening organ dysfunction caused by dysregulated host response to infection, is leading cause of death in intensive care units. The development sepsis-associated (SAOD) poses threat the survival patients with sepsis. Unfortunately, pathogenesis sepsis and SAOD complicated, multifactorial, has not been completely clarified. Recently, numerous studies have demonstrated that pyroptosis, which characterized inflammasome caspase activation cell membrane pore formation, involved Unlike apoptosis, pyroptosis pro-inflammatory form programmed participates regulation immunity inflammation. Related shown sepsis, moderate promotes clearance pathogens, whereas excessive leads immune disorders SAOD. Additionally, transcription factors, non-coding RNAs, epigenetic modifications post-translational can directly or indirectly regulate pyroptosis-related molecules. Pyroptosis also interacts autophagy, NETosis, necroptosis. This review summarizes roles regulatory mechanisms As our understanding functions improves, new diagnostic biomarkers targeted therapies associated improve clinical outcomes appears promising future.

Language: Английский

Citations

39
NLRP3 inflammasome-driven IL-1β and IL-18 contribute to lipopolysaccharide-induced septic cardiomyopathy DOI
Kenta Fujimura, Tadayoshi Karasawa, Takanori Komada

et al.

Journal of Molecular and Cellular Cardiology, Journal Year: 2023, Volume and Issue: 180, P. 58 - 68

Published: May 11, 2023

Language: Английский

Citations

36
Autophagy in sarcopenia: Possible mechanisms and novel therapies DOI Open Access

Guangyang Xie,

Hongfu Jin, Herasimenka Mikhail

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 165, P. 115147 - 115147

Published: July 18, 2023

With global population aging, age-related diseases, especially sarcopenia, have attracted much attention in recent years. Characterized by low muscle strength, quantity or quality and physical performance, sarcopenia is one of the major factors associated with an increased risk falls disability. Much effort has been made to understand cellular biological physiological mechanisms underlying sarcopenia. Autophagy important self-protection mechanism that relies on lysosomes degrade misfolded proteins damaged organelles. Research designed obtain new insight into human diseases from autophagic aspect carried out progress, which encourages relevant studies relationship between autophagy plays a protective role modulating regenerative capability satellite cells, relieving oxidative stress suppressing inflammatory response. This review aims reveal specific interaction explore possible therapies hopes encouraging more research need unlocking novel promising ameliorate

Language: Английский

Citations

25
Malvidin alleviates mitochondrial dysfunction and ROS accumulation through activating AMPK-α/UCP2 axis, thereby resisting inflammation and apoptosis in SAE mice DOI Creative Commons
Panpan Zhao, Xiaomin Li,

Qiankun Yang

et al.

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 13

Published: Jan. 9, 2023

This study aimed to explore the protective roles of malvidin in life-threatened sepsis-associated encephalopathy (SAE) and illustrate underlying mechanism. SAE mice models were developed treated with for subsequently effects evaluation. Malvidin restored neurobehavioral retardation, declined serum S100β NSE levels, sustained cerebrum morphological structure, improved blood-brain barrier integrity elevated tight junction proteins, decreased evans blue leakage, finally protect from brain injury. Mechanistically, prevented mitochondrial dysfunction enhanced JC-1 aggregates ATP ROS accumulation lipid peroxidation increased antioxidant enzymes. UCP2 protein levels found be after LPS stimulation BV-2 cells, recovered its a dependent manner. In vivo inhibition genipin or vitro interference siRNA both disrupted membrane potential, intensified DCF signals, being key target malvidin. Moreover, dorsomorphin block assays verified that upregulated expression through phosphorylating AMPK models. Also, alleviated progression ROS-dependent NLRP3 inflammasome activation mediated pro-inflammatory cytokines secretion pathway apoptosis weakened body formation tunel positive Bax, cytochrome C, caspase-3 Bcl-2 levels. Overall, this illustrated targeted AMPK-α/UCP2 axis restore LPS-induced alleviate accumulation, which further inhibits way, ultimately protected mice, providing reference development prophylactic approach.

Language: Английский

Citations

23
Cardiomyocyte peroxisome proliferator-activated receptor α prevents septic cardiomyopathy via improving mitochondrial function DOI
Xinxin Zhu, Xia Wang,

Shiyu Jiao

et al.

Acta Pharmacologica Sinica, Journal Year: 2023, Volume and Issue: 44(11), P. 2184 - 2200

Published: June 16, 2023

Language: Английский

Citations

23